Bipolar Disorder (BD) is a severe psychiatric illness that is hallmarked by manic and depressive states. Inhibitory deficits are characteristic of BD and occur throughout the various phases of the illness. Problems with inhibition in people with BD may result in increased risk-taking behavior as well as difficulties in completing important tasks of daily living and complying with treatment. Consequently, studying profiles of disinhibition throughout the BD spectrum may elucidate traits of the disease that are present regardless of symptomatology. Furthermore, inhibitory deficits can be studied in both humans and animals using parallel methodology, thus contributing to the development of much-needed animal models of BD mania. During the past funding period, a novel technology was developed to study inhibitory deficits in humans (the human Behavioral Pattern Monitor: hBPM). Manic BD patients exhibited a "signature" pattern of inhibitory deficits that distinguished them from schizophrenia and nonpatient subjects. Furthermore, selective manipulation of the dopamine transporter in mice, either genetically (knockdown mice) or pharmacologically (GBR12909 administration), uniquely matched the inhibitory profile of manic BD patients. The present application seeks to test whether the inhibitory profile found among manic BD patients is specific to the manic state or persists during the other phases of BD, i.e., euthymic, depressed, and hypomanic states. Additionally, this investigation will examine multiple aspects of cognitive inhibition in a cross-species fashion. BD participants in various phases of their illness will be tested with the hBPM to measure hyperactivity and disinhibited exploration, the Conner's Continuous Performance Test to assess attentional inhibition, the Iowa Gambling Task to assess risk-taking inhibition, and the Wisconsin Card Sorting Task to assess perseverative inhibition. Mice will be tested in an analogous rodent BPM paradigm and in recently developed mouse versions of the three measures of cognitive inhibition listed above. In keeping with this program's cross-species translational approach, in which human studies inform animal investigations and animal studies inform the next logical step in the human work, an additional aim is to test whether pharmacological manipulations in healthy humans can mimic aspects of the manic BD profile. Thus, inhibitory functioning will be assessed in healthy non-patient subjects using dopamine agonist compounds (amphetamine and modafinil) and compared to a non-dopaminergic stimulant (caffeine) and placebo. These drugs will also be tested in the parallel mouse paradigms to examine the predictive validity of the rodent tasks. Finally, the BD mouse models will be tested at baseline and in response to antipsychotic and antimanic treatments using the cognitive and behavioral paradigms mentioned above. Studying human and parallel animal models of BD will facilitate the refinement of translational models, evaluate putative target endophenotypes, and identify behavioral biomarkers for use in proof-of-concept studies assessing the potential efficacy of novel therapeutic interventions for BD. PUBLIC HEALTH RELEVANCE: Individuals with Bipolar Disorder (BD) have significant difficulty in inhibiting their thoughts and behavior, which adversely impacts their ability to carry out daily activities and resume independent functioning, even when they are not actively ill. This application aims to measure inhibition across the multiple phases of BD and also to study human and animal models of the disease in parallel. Completion of this work will assist in understanding the underlying brain dysfunction of BD as well as assist in discovering and developing novel treatments.